Co-targeting the PI3K/mTOR and JAK2 signalling pathways produces synergistic activity against myeloproliferative...

Area of Science:

• Oncology
• Hematology
• Molecular Biology

Background:

• Aberrant Janus kinase 2 (JAK2) signaling is a key driver in myeloproliferative neoplasms (MPN).
• Current JAK2 inhibitors are not mutation-specific and struggle to eradicate neoplastic clones.
• Targeting multiple signaling pathways simultaneously may offer a more effective treatment strategy for MPN.

Purpose of the Study:

• To investigate the efficacy of BEZ235, a dual phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor, as a single agent and in combination with ruxolitinib (a JAK1/JAK2 inhibitor).
• To evaluate this combination therapy in various preclinical models of MPN.

Main Methods:

• In vitro studies using JAK2V617F-mutated and wild-type mouse and human cell lines.
• Colony formation assays with progenitor cells from JAK2V617F knock-in mice and MPN patients.
• In vivo studies using immunodeficient mice xenograft models and conditional JAK2V617F knock-in mice.

Main Results:

• Single-agent BEZ235 preferentially inhibited proliferation, induced cell cycle arrest, and apoptosis in JAK2V617F-mutated cells.
• BEZ235 and ruxolitinib combination therapy demonstrated significant synergistic effects in vitro.
• Combined treatment effectively reduced disease burden, prolonged survival in mouse models, and improved key disease markers like spleen size and reticulocyte count.

Conclusions:

• Combined inhibition of PI3K/mTOR and JAK2 signaling pathways presents a potent therapeutic strategy for MPN.
• This dual-targeting approach warrants further investigation as a novel treatment for myeloproliferative neoplasms.